| 1. |
- Eriksson, Olof, et al.
(författare)
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Quantitative Imaging of Serotonergic Biosynthesis and Degradation in the Endocrine Pancreas
- 2014
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Ingår i: Journal of Nuclear Medicine. - : Society of Nuclear Medicine. - 0161-5505 .- 1535-5667 .- 2159-662X. ; 55:3, s. 460-465
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Tidskriftsartikel (refereegranskat)abstract
- Serotonergic biosynthesis in the endocrine pancreas, of which the islets of Langerhans is the major constituent, has been implicated in insulin release and β cell proliferation. In this study, we investigated the feasibility of quantitative noninvasive imaging of the serotonergic metabolism in the pancreas using the PET tracer (11)C-5-hydroxy-l-tryptophan ((11)C-5-HTP).METHODS: Uptake of (11)C-5-HTP, and its specificity for key enzymes in the serotonergic metabolic pathway, was assessed in vitro (INS-1 and PANC1 cells and human islet and exocrine preparations) and in vivo (nonhuman primates and healthy and diabetic rats).RESULTS: In vitro tracer uptake in endocrine cells (INS-1 and human islets), but not PANC1 and exocrine cells, was mediated specifically by intracellular conversion into serotonin. Pancreatic uptake of (11)C-5-HTP in nonhuman primates was markedly decreased by inhibition of the enzyme dopa decarboxylase, which converts (11)C-5-HTP to (11)C-serotonin and increased after inhibition of monoamine oxidase-A, the main enzyme responsible for serotonin degradation. Uptake in the rat pancreas was similarly modulated by inhibition of monoamine oxidase-A and was reduced in animals with induced diabetes.CONCLUSION: The PET tracer (11)C-5-HTP can be used for quantitative imaging of the serotonergic system in the endocrine pancreas.
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| 2. |
- Eriksson, Olof, et al.
(författare)
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The Positron Emission Tomography ligand [11C]5-Hydroxy-Tryptophan can be used as a surrogate marker for the human endocrine pancreas
- 2014
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Ingår i: Diabetes. - : American Diabetes Association. - 0012-1797 .- 1939-327X. ; 63:10, s. 3428-3437
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Tidskriftsartikel (refereegranskat)abstract
- In humans a well-developed serotonin system is localized to the pancreatic islets while being absent in exocrine pancreas. Assessment of pancreatic serotonin biosynthesis could therefore be used to estimate the human endocrine pancreas. Proof of concept was tested in a prospective clinical trial by comparisons of type 1 diabetic (T1D) patients, with extensive reduction of beta cells, with healthy volunteers (HV).C-peptide negative (i.e. insulin-deficient) T1D subjects (n=10) and HV (n=9) underwent dynamic Positron Emission Tomography with the radiolabeled serotonin precursor [(11)C]5-Hydroxy-Tryptophan ([(11)C]5-HTP).A significant accumulation of [(11)C]5-HTP was obtained in the pancreas of the HV, with large inter-individual variation. A substantial and highly significant reduction (66%) in the pancreatic uptake of [(11)C]5-HTP in T1D subjects was observed, and this was most evident in the corpus and caudal regions of the pancreas where beta-cells normally are the major constituent of the islets.[(11)C]5-HTP retention in the pancreas was reduced in T1D compared to non-diabetic subjects. Accumulation of [(11)C]5-HTP in the pancreas of both HV and subjects with T1D were in agreement with previously reported morphological observations on the beta cell volume implying that [(11)C]5-HTP retention is a useful non-invasive surrogate marker for the human endocrine pancreas.
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| 3. |
- Aldenlöv, Jens
(författare)
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Exploring Public Procurement of Swedish Railway Infrastructure Maintenance
- 2019
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Licentiatavhandling (övrigt vetenskapligt/konstnärligt)abstract
- In 2002, Sweden started to outsource its railway infrastructure maintenance. Through gradual exposure (i.e. outsourcing one contract area at a time), the Swedish Transport Administration has developed its competence of being a client towards its contractors. The last contract was outsourced in 2014. In the last decade, the development of governance techniques and maintenance cost has not matched the increase in traffic. Due to an increased awareness in environmentally friendlier transportation, traffic is only expected to increase further in the coming years. Governance techniques and maintenance cost ultimately depends on the client-contractor relationship through public procurement. Hence, there is a need to understand public procurement of railway infrastructure maintenance. Therefore, the purpose of this thesis is to contribute to the knowledge of public procurement of railway infrastructure maintenance. Three separate studies were conducted. Study 1 was a literature review to explore and determine the state-of-the-art for the field of public procurement of railway maintenance. Study 2 was a linear regression analysis to examine the relationship between contract design and the output of maintenance in Sweden. Study 3 was an interview study in Sweden that explored what factors that supports or hinders collaboration in railway maintenance.The main results of these studies are that asset knowledge is important for both the client and the contractor. Through reliable asset knowledge, incentives and contracts can be designed to support governance and collaboration. Today, railway infrastructure maintenance is dominated by informal relationships that lack the support of formal partnering activities. When an informal relationship is supported by a formal structure it provides a basis for innovation. This formal structure should be centralized around gaining and sharing asset knowledge. By establishing such a system to increase the asset knowledge and supporting collaboration, public organizations of maintenance can provide a basis for the improvement of maintenance.
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| 4. |
- Engman, Jakob, et al.
(författare)
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Neisseria meningitidis Polynucleotide Phosphorylase Affects Aggregation, Adhesion, and Virulence
- 2016
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 84:5, s. 1501-1513
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Tidskriftsartikel (refereegranskat)abstract
- Neisseria meningitidis autoaggregation is an important step during attachment to human cells. Aggregation is mediated by type IV pili and can be modulated by accessory pilus proteins, such as PilX, and posttranslational modifications of the major pilus subunit PilE. The mechanisms underlying the regulation of aggregation remain poorly characterized. Polynucleotide phosphorylase ( PNPase) is a 3'-5' exonuclease that is involved in RNA turnover and the regulation of small RNAs. In this study, we biochemically confirm that NMC0710 is the N. meningitidis PNPase, and we characterize its role in N. meningitidis pathogenesis. We show that deletion of the gene encoding PNPase leads to hyperaggregation and increased adhesion to epithelial cells. The aggregation induced was found to be dependent on pili and to be mediated by excessive pilus bundling. PNPase expression was induced following bacterial attachment to human cells. Deletion of PNPase led to global transcriptional changes and the differential regulation of 469 genes. We also demonstrate that PNPase is required for full virulence in an in vivo model of N. meningitidis infection. The present study shows that PNPase negatively affects aggregation, adhesion, and virulence in N. meningitidis.
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| 5. |
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| 6. |
- Eriksson, Jens, et al.
(författare)
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Characterization of motility and piliation in pathogenic Neisseria
- 2015
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Ingår i: BMC Microbiology. - : Springer Science and Business Media LLC. - 1471-2180. ; 15
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Tidskriftsartikel (refereegranskat)abstract
- Background: The type IV pili (Tfp) of pathogenic Neisseria (i. e., N. gonorrhoeae and N. meningitidis) are essential for twitching motility. Tfp retraction, which is dependent on the ATPase PilT, generates the forces that move bacteria over surfaces. Neisseria motility has mainly been studied in N. gonorrhoeae whereas the motility of N. meningitidis has not yet been characterized. Results: In this work, we analyzed bacterial motility and monitored Tfp retraction using live- cell imaging of freely moving bacteria. We observed that N. meningitidis moved over surfaces at an approximate speed of 1.6 mu m/s, whereas N. gonorrhoeae moved with a lower speed (1.0 mu/s). An alignment of the meningococcal and gonococcal pilT promoters revealed a conserved single base pair variation in the -10 promoter element that influence PilT expression. By tracking mutants with altered pilT expression or pilE sequence, we concluded that the difference in motility speed was independent of both. Live-cell imaging using total internal reflection fluorescence microscopy demonstrated that N. gonorrhoeae more often moved with fewer visible retracting filaments when compared to N. meningitidis. Correspondingly, meningococci also displayed a higher level of piliation in transmission electron microscopy. Nevertheless, motile gonococci that had the same number of filaments as N. meningitidis still moved with a lower speed. Conclusions: These data reveal differences in both speed and piliation between the pathogenic Neisseria species during twitching motility, suggesting a difference in Tfp-dynamics.
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| 7. |
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| 8. |
- Eriksson, Jens, 1980-, et al.
(författare)
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Difference in twitching motility between Neisseria meningitidis and Neisseria gonorrhoeae and its relation to pilus dynamics
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- Type IV pili of pathogenic Neisseria, i. e. Neisseria gonorrhoeae and Neisseria meningitidis, are essential for initial attachment to host cells, induction of signal transduction cascades and disease development. A characteristic feature of type IV pili is their ability to retract, which generates forces that move bacteria over surfaces. However, the relation between bacterial motility and pilus dynamics remains poorly understood. In this work we analyzed bacterial motility and monitored movement of fluorescently labeled pili by live cell imaging. We found that movement of N. meningitidis occurred at higher speed and with a larger number of retracting pili than for N. gonorrhoeae. Analysis of time-lapse images suggested that N. gonorrhoeae most often moved using one retracting pilus, whereas N. meningitidis most often used four pili. There were no differences in the membrane distribution of PilT among strains. However, we found significantly higher levels of PilT in N. gonorrhoeae than in N. meningitidis. This produces a higher retraction probability, which could contribute to explaining the lower number of pili observed in N. gonorrhoeae. Finally, we propose a mechanism for how the speed of bacterial movement on a surface depends on the number of retracting pili.
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| 9. |
- Eriksson, Jens, et al.
(författare)
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Loss of Meningococcal PilU Delays Microcolony Formation and Attenuates Virulence In Vivo
- 2012
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Ingår i: Infection and Immunity. - 0019-9567 .- 1098-5522. ; 80:7, s. 2538-2547
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Tidskriftsartikel (refereegranskat)abstract
- Neisseria meningitidis is a major cause of sepsis and bacterial meningitis worldwide. This bacterium expresses type IV pili (Tfp), which mediate important virulence traits such as the formation of bacterial aggregates, host cell adhesion, twitching motility, and DNA uptake. The meningococcal PilT protein is a hexameric ATPase that mediates pilus retraction. The PilU protein is produced from the pilT-pilU operon and shares a high degree of homology with PilT. The function of PilT in Tfp biology has been studied extensively, whereas the role of PilU remains poorly understood. Here we show that pilU mutants have delayed microcolony formation on host epithelial cells compared to the wild type, indicating that bacterium-bacterium interactions are affected. In normal human serum, the pilU mutant survived at a higher rate than that for wild-type bacteria. However, in a murine model of disease, mice infected with the pilT mutant demonstrated significantly reduced bacterial blood counts and survived at a higher rate than that for mice infected with the wild type. Infection of mice with the pilU mutant resulted in a trend of lower bacteremia, and still a significant increase in survival, than that of the wild type. In conclusion, these data suggest that PilU promotes timely microcolony formation and that both PilU and PilT are required for full bacterial virulence.
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| 10. |
- Eriksson, Olof, et al.
(författare)
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Detection of Metastatic Insulinoma by Positron Emission Tomography with [(68)Ga]Exendin-4 - : a case report
- 2014
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 99:5, s. 1519-1524
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Tidskriftsartikel (refereegranskat)abstract
- Context: Insulinomas are the most common cause of endogenous hyperinsulinaemic hypoglycaemia in non-diabetic adult patients. They are usually benign and curative surgery is the "gold standard" treatment if they can be localized. Malignant insulinomas are seen in less than 10% and their prognosis is poor. The Glucagon Like Peptide-1 receptor (GLP-1R) is markedly upregulated in insulinomas - especially benign lesions which are difficult to localize with current imaging techniques.Objective:To assess the possibility of the detection of primary and metastatic insulinoma by PET using [(68)Ga]Ga-DO3A-VS-Cys(40)-Exendin-4 ([(68)Ga]Exendin-4) in a patient with severe hypoglycemia.Design:Dynamic and static PET/CT examination of a patient using [68Ga]Exendin-4.Setting:Uppsala University Hospital, Uppsala, Sweden.Patients:A patient presented with hypoglycemia requiring continuous intravenous glucose infusions. A pancreatic insulinoma was suspected and an exploratory laparotomy was urgently performed. At surgery, a tumor in the pancreatic tail with an adjacent metastasis was found and a distal pancreatic resection (plus splenectomy) and removal of lymph node was performed. Histopathology showed a WHO grade II insulinoma. Postoperatively hypoglycemia persisted but a PET/CT examination using the neuroendocrine marker [(11)C]-5-hydroxy-L-tryptophan was negative.Interventions:The patient was administered with [(68)Ga]Exendin-4 and examined by dynamic PET over the liver and pancreas.Main Outcome Measures:N/AResults:The stable GLP-1 analogue Exendin-4 was labeled with (68)Ga for PET imaging of GLP-1R expressing tumors. The patient was examined by [(68)Ga]Exendin-4-PET/CT which confirmed several small GLP-1R positive lesions in the liver and a lymph node that could not be conclusively identified by other imaging techniques. The results obtained from the [(68)Ga]Exendin-4-PET/CT examination provided the basis for continued systemic treatment.Conclusion:The results of the [(68)Ga]Exendin-4-PET/CT examination governed the treatment strategy of this particular patient and demonstrated the potential of this technique for future management of patients with this rare, but potentially fatal disease.
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